The Medicines Company to Present New Data from TANGO II Study of VABOMERE™ (meropenem and vaborbactam) at IDWeek 2017
The Medicines Company (NASDAQ:MDCO) today announced that new data from its TANGO II study of VABOMERE (meropenem and vaborbactam) will be presented this week at IDWeek 2017 in San Diego.
In the TANGO II study, VABOMERE was associated with a higher clinical cure versus “best available therapy” (BAT) in patients with a baseline organism that was carbapenem-resistant Enterobacteriaceae (mCRE-MITT population) at both end-of-therapy (EOT) (VABOMERE 64.3% vs. BAT 33.3%; p=0.04) and test-of-cure (TOC) (VABOMERE 57.1% vs. BAT 26.7%; p=0.04). In immunocompromised patients, VABOMERE was also associated with a higher clinical cure versus BAT at EOT (VABOMERE 60% vs. BAT 12.5%; p<0.01), as well as lower mortality.
VABOMERE was associated, across all patients, with decreased nephrotoxicity and fewer treatment-related adverse events versus BAT. An analyses using the composite endpoints of clinical failure or nephrotoxicity demonstrated a risk-benefit profile favoring VABOMERE versus BAT (32.1% VABOMERE vs 80.0% BAT (95% CI: ?74.5 to ?21.2; P< 0.001)).
In July 2017, randomization in the TANGO II study was stopped early, following a recommendation by the TANGO II Independent Data Safety Monitoring Board (DSMB), based on an analysis of 72 patients, including 43 patients with microbiologically evaluable carbapenem-resistant Enterobacteriaceae (CRE) infections of blood, lung, urinary tract and abdominal organs. The DSMB recommended, based on risk-benefit considerations, that randomization of additional patients to the best available therapy comparator arm should not continue.
VABOMERE was recently approved by the U.S. Food and Drug Administration (FDA) for the treatment of adult patients with complicated urinary tract infections (cUTI), including pyelonephritis, caused by designated susceptible Enterobacteriaceae – Escherichia coli, Klebsiella pneumoniae and Enterobacter cloacae species complex. The Medicines Company plans to begin sales and distribution of VABOMERE in the fourth quarter of 2017 and has set a $990 price per day of therapy.
“We are excited that the TANGO II data affirm our intention to continue the development of VABOMERE to address serious infections due to Klebsiella pneumoniae carbapenemase (KPC)-producing CRE,” said Tony Kingsley, President and Chief Operating Officer of The Medicines Company. “Infections due to CRE are increasing in all settings of care in the United States. Patients are often treated with combination therapies of older antibiotics, many of which have significant toxicities, most notably renal toxicity. VABOMERE was specifically designed and developed to address this growing public health threat. We look forward to sharing the TANGO II results with regulatory authorities.”
Michael Dudley, PharmD, FIDSA, Senior Vice President, Head of R&D and Co-Leader of The Medicines Company’s Infectious Disease Business added, “CRE is considered an urgent antimicrobial resistant threat by the U.S. Centers for Disease Control and Prevention (CDC), and the World Health Organization (WHO) considers new drugs for CRE to be a critical priority. VABOMERE addresses this need by restoring the activity of meropenem by combining it with vaborbactam, a novel, first-in-class beta lactamase inhibitor designed to inhibit KPC enzymes that are largely responsible for resistance to carbapenems in Enterobacteriaceae in the United States.”
Cornelius Clancy M.D., Associate Professor in the Division of Infectious Diseases at University of Pittsburgh and Chief of Infectious Diseases at the VA Pittsburgh Health System summarized, “The totality and consistency of the data from the TANGO programs, particularly the landmark study TANGO II, are compelling. TANGO II showed VABOMERE was associated with a higher clinical cure rate versus BAT in difficult to treat infections and patient populations. The microbiological and pharmacological underpinnings of this combination product based on meropenem have been translated into an important advance for patients and clinicians.”
A total of nine posters on VABOMERE, including comprehensive analyses from the TANGO II study, are now available to IDWeek registrants and will be presented on Friday, October 6th and Saturday, October 7th. The electronic versions of posters can be accessed on The Medicines Company website at http://www.themedicinescompany.com/investors/events.
Summaries of the key findings from poster presentations, as detailed in the IDWeek 2017 schedule, are as follows:
1862: Clinical Outcomes of Serious Infections due to Carbapenem-Resistant Enterobacteriaceae (CRE) in TANGO II, a Phase 3, Randomized, Multi-National, Open-Label Trial of Meropenem-Vaborbactam (M-V) vs. Best Available Therapy (BAT) - VABOMERE monotherapy was associated with a higher rate of clinical cure compared to BAT at both EOT and TOC across all infection types in the mCRE-MITT population. At EOT, clinical cure was 64.3% for VABOMERE versus 33.3% for BAT (p=0.04). At TOC, clinical cure was 57.1% for VABOMERE versus 26.7% for BAT (p=0.04).
VABOMERE was associated with fewer treatment-related adverse events (AEs) versus BAT (VABOMERE 24.4% vs. BAT 44.0%) and decreased nephrotoxicity as evidenced by serum creatinine increase ?0.5 mg/dL (VABOMERE 11.1% vs. BAT 24.0%). An exploratory analyses using the composite endpoints of clinical failure or nephrotoxicity demonstrated a risk-benefit profile favoring VABOMERE versus BAT (32.1% VABOMERE vs 80.0% BAT (95% CI: ?74.5 to ?21.2; p < 0.001)).
1867: Meropenem-Vaborbactam vs. Best Available Therapy for Carbapenem-Resistant Enterobacteriaceae Infections in TANGO II: Primary Outcomes by Site of Infection – At EOT/TOC, VABOMERE showed clinical cure of 50% to 58% vs. 25% to 37.5% with BAT in mCRE-MITT patients with bacteremia. Mortality at 28 days in the pooled patient population with bacteremia, hospital-acquired bacterial pneumonia (HABP) or ventilator-associated bacterial pneumonia (VABP) was 25% for VABOMERE vs. 44% for BAT (43.7% reduction). In patients with complicated urinary tract infections/acute pyelonephritis (cUTI/AP), the overall success at EOT was 72.7% for VABOMERE compared to 50% for BAT; success at TOC was 42.9% vs. 50% for VABOMERE and BAT, respectively.
1868: Meropenem-Vaborbactam vs. Best Available Therapy for Carbapenem-Resistant Enterobacteriaceae Infections in TANGO II: Outcomes in Immunocompromised Patients - Approximately 40% of patients with CRE in TANGO II were immunocompromised (n=18). Treatment of these immunocompromised CRE patients with VABOMERE was associated with higher clinical cure rate (60% vs. 12.5%; P=0.01) and lower mortality (20% vs. 37%) than BAT. Among immunocompromised subjects, when compared to BAT, VABOMERE was associated with fewer AEs (84.6% vs. 100%), drug-related AEs (30.8% vs. 40.0%), serious AEs (38.5% vs. 50.0%), discontinuations of study drug or study due to AEs (15.4% vs. 30.0%) and renal-related AEs (7.7% vs. 40.0%).
Poster 1874: Assessment of MIC Increases with Meropenem-Vaborbactam and Ceftazidime-Avibactam in TANGO II (a Phase 3 Study of the Treatment of CRE Infections). The objective of this study was to examine the minimum inhibitory concentration (MIC) increases with meropenem-vaborbactam and ceftazidime-avibactam in patients with KPC-producing CRE enrolled in the TANGO II trial that were treated with these agents. One patient treated with VABOMERE had a fourfold change in MIC detected in a post-treatment bacterial isolate; this change remained in the susceptible range for VABOMERE (MIC ? 4 ug/ml). One of four patients treated with ceftazidime-avibactam monotherapy as BAT had a 256-fold change in MIC that became resistant to ceftazidime-avibactam (MIC > 128 ug/ml), with mutations in the KPC enzyme similar to those recently reported by other investigators.
Poster 1835: Meropenem-Vaborbactam Pharmacokinetics in Subjects with Chronic Renal Impairment, Including Hemodialysis. Meropenem and vaborbactam pharmacokinetics were determined following a single dose to subjects with varying degrees of renal impairment, including patients undergoing hemodialysis. The changes in the pharmacokinetics of meropenem and vaborbactam were similar for patients with mild to severe renal impairment, with the relationship between drug clearance and estimated glomerular filtration rate (eGFR) for meropenem and vaborbactam were similar, allowing for dosage reduction in renal impairment having a similar proportional reduction for each component. Hemodialysis removes both meropenem and vaborbactam from plasma, and thus a maintenance dose of VABOMERE is required after a dialysis session.
Poster 1852: Meropenem-Vaborbactam Pharmacokinetic-Pharmacodynamic (PK-PD) Target Attainment Analyses as Support for Dose Selection in Patients with Normal Renal Function and Varying Degrees of Renal Impairment. Dosage regimens of VABOMERE in FDA-approved labeling for patients with normal renal function and varying levels of renal impairment were evaluated in a simulation study to determine if plasma exposures of meropenem and vaborbactam would achieve PK-PD targets for efficacy derived from nonclinical models of infection. Plasma pharmacokinetics using a population PK model derived from data from the Phase I and Phase III studies were used. The results show that over 90% of patients achieve target exposures of both drugs for KPC-producing Enterobacteriaceae with VABOMERE MICs up to 8 ug/ml.
Poster 1879: Meropenem-Vaborbactam: Outcomes in Subjects with Renal Impairment in Phase 3 Studies TANGO I and II. The efficacy of some recently approved beta-lactamase inhibitor combinations has been noted to decrease in patients with moderate renal impairment. This poster examined safety and efficacy in subsets of patients with renal impairment treated with VABOMERE in the TANGO I and TANGO II studies. In TANGO I and II, 11.5% and 20.9% of patients had a baseline creatinine clearance of less than 50 ml/min, respectively. In TANGO I, overall success in patients with creatinine clearance < 50 ml/min at the end of IV treatment was 100% in VABOMERE treated patients compared to 90.9% for piperacillin-tazobactam; these values in patients with a creatinine clearance > 50 ml/min were 98.2% vs. 94.3% for VABOMERE and piperacillin/tazobactam, respectively. In TANGO II, the clinical cure at EOT in patients in the mCRE-mMITT population with renal impairment (creatinine clearance < 50 ml/min) was 40% vs. 25% for VABOMERE and piperacillin/tazobactam, respectively.
Poster 1234: Activity of Meropenem-Vaborbactam Against Enterobacteriaceae Isolates Carrying bla-KPC Collected Worldwide. Over 34,000 clinical isolates of Enterobacteriaceae collected during 2014-2016 from the worldwide SENTRY surveillance were tested for susceptibility to VABOMERE. KPC- producing isolates were detected in 17 countries and the incidence ranged from 0.1% to 11.3% of all Enterobacteriaceae, depending on the country. Meropenem-vaborbactam inhibited 98.6% of isolates at FDA-approved breakpoints (MIC <= 4 ug/ml), with an MIC50/90 of 0.12/1 ug/ml.
Poster 1866: Meropenem-Vaborbactam (VABOMERE) vs. Piperacillin-Tazobactam in TANGO I (a Phase 3, Randomized, Double-blind Trial): Outcomes by Baseline MIC in Adults with cUTI or AP. This poster examined the relation between MIC to VABOMERE or piperacillin/tazobactam to determine if the MIC or non-susceptibility to piperacillin/tazobactam was associated with clinical cure or microbial eradication in TANGO-1. Microbial eradication at end of intravenous treatment (EOIVT) in patients treated with piperacillin/tazobactam who had a non-susceptible Enterobacteriaceae at baseline was 26/30 (86.7%) vs. 116/124 (93.5%) in those with a susceptible organism (P>0.1). There was no relation between piperacillin/tazobactam or VABOMERE MIC and clinical cure of microbial eradication.
VABOMERE™ (meropenem and vaborbactam) is indicated for the treatment of patients 18 years of age and older with complicated urinary tract infections (cUTI), including pyelonephritis caused by the following susceptible microorganisms: Escherichia coli, Klebsiella pneumoniae, and Enterobacter cloacae species complex.
To reduce the development of drug-resistant bacteria and maintain the effectiveness of VABOMERE and other antibacterial drugs, VABOMERE should be used only to treat or prevent infections that are proven or strongly suspected to be caused by susceptible bacteria.
IMPORTANT SAFETY INFORMATION
VABOMERE is contraindicated in patients with known hypersensitivity to any components of VABOMERE (meropenem and vaborbactam), or to other drugs in the same class or in patients who have demonstrated anaphylactic reactions to beta-lactam antibacterial drugs.
Warnings and Precautions
- Hypersensitivity reactions were reported in patients treated with VABOMERE in the clinical trials. Serious and occasionally fatal hypersensitivity (anaphylactic) reactions and serious skin reactions have been reported in patients receiving therapy with beta-lactam antibacterial drugs. There have been reports of individuals with a history of penicillin hypersensitivity who have experienced severe hypersensitivity reactions when treated with another beta-lactam antibacterial drug. If an allergic reaction to VABOMERE occurs, discontinue the drug immediately.
- Seizures and other adverse Central Nervous System (CNS) experiences have been reported during treatment with meropenem, which is a component of VABOMERE. Close adherence to the recommended dosage regimens is urged, especially in patients with known factors that predispose to convulsive activity.
- Clostridium difficile-associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including VABOMERE, and may range in severity from mild diarrhea to fatal colitis. Careful medical history is necessary since CDAD has been reported to occur over two months after the administration of antibacterial agents. If CDAD is suspected or confirmed, ongoing antibacterial drug use not directed against C. difficile may need to be discontinued.
- The concomitant use of VABOMERE and valproic acid or divalproex sodium is generally not recommended. Case reports in the literature have shown that co-administration of carbapenems, including meropenem, to patients receiving valproic acid or divalproex sodium results in a reduction in valproic acid concentrations. The valproic acid concentrations may drop below the therapeutic range as a result of this interaction, therefore increasing the risk of breakthrough seizures. If administration of VABOMERE is necessary, consider supplemental anticonvulsant therapy.
- In patients with renal impairment, thrombocytopenia has been observed in patients treated with meropenem, but no clinical bleeding has been reported.
- Alert patients receiving VABOMERE on an outpatient basis regarding adverse reactions such as seizures, delirium, headaches and/or paresthesias that could interfere with mental alertness and/or cause motor impairment.
- Prescribing VABOMERE in the absence of a proven or strongly suspected bacterial infection is unlikely to provide benefit to the patient and increases the risk of drug-resistant bacteria.
- As with other antibacterial drugs, prolonged use of VABOMERE may result in overgrowth of nonsusceptible organisms.
The most frequently reported adverse reactions occurring in ?3% of patients treated with VABOMERE were headache, phlebitis/infusion site reactions, and diarrhea.
Please see www.vabomere.com for the full prescribing information.
About TANGO II
TANGO II is a multi-center, randomized, open-label Phase III clinical trial of VABOMERE versus “best available therapy” in patients with serious infections (cUTI, bacteremia, HABP/VABP, and complicated intraabdominal infections) suspected or documented to be caused by CRE. Patients with CRE were randomized to receive either VABOMERE monotherapy or the “best available therapy” for up to 14 days. Patients randomized to the best available therapy arm of the trial were given antimicrobial therapy often consisting of two to four drugs used in combination; this treatment was selected for each patient by the investigator based on available clinical laboratory and other patient data, and thus represents the current standard of care used for the treatment of CRE infections.
In July 2017, randomization in the trial was stopped early, following a recommendation by the TANGO II DSMB, based on an analysis of 72 patients, including 43 patients with microbiologically evaluable CRE infections of blood, lung, urinary tract and abdominal organs. Of the 72 patients enrolled in the TANGO II study, 28 were treated with VABOMERE and 15 with BAT. The most common pathogen was Klebsiella pneumoniae (86%). The DSMB recommended, based on risk-benefit considerations, that randomization of additional patients to the best available therapy comparator arm should not continue. The Company plans to enroll patients into an amended, single-arm study protocol for treatment with VABOMERE at selected study sites.
About Carbapenem-Resistant Enterobacteriaceae (CRE)
Enterobacteriaceae comprise a family of gram-negative bacteria that includes Klebsiella sp., E. coli, Enterobacter sp. and others. This group of bacteria collectively are largely responsible for hospital-acquired infections due to gram-negative bacteria. Enterobacteriaceae have become increasingly resistant to the widely used beta-lactam class of antibiotics due to production of enzymes known as beta-lactamases that degrade these antibiotics. The worldwide dissemination of newer beta-lactamases known as carbapenemases has been responsible for resistance to the carbapenem and other classes of antibiotics. In the United States, the Klebsiella pneumoniae carbapenemase (KPC) enzyme is responsible for over 90% of carbapenemase mediated resistance in CRE. The Company estimates, based on data derived from public sources and internal research, that there are over 60,000 patients with CRE infections annually in the United States.
Patients at risk for CRE infections include those with prior colonization, the institutionalized elderly, immunocompromised patients, mechanically ventilated patients, use of prior antibiotics, and those with multiple underlying comorbidities. Infections due to CRE are associated with high antibiotic failure rates, high mortality (up to 50%), and high cost to hospitals, third party payers, and society (which could range from $10,000-$84,000 per episode).
Due to the paucity of antibiotics with activity against CRE pathogens, clinicians are often forced to treat CRE infections, such as cUTIs, with combinations of antibiotics that had been sparingly used over the past two decades.
In light of the poor outcomes associated with CRE infections and the critical role of carbapenem antibiotics for treatment of resistant gram negative infections, CRE is considered an urgent antimicrobial resistance threat by the United States CDC, and the WHO recently designated development of new drugs for CRE to be a critical priority.
About The Infectious Disease Business
The Medicines Company Infectious Disease Business (MDCO IDC) is committed to bringing life-saving antimicrobial products to patients with the most serious drug-resistant infections – infections caused by “super bugs” which are no longer treatable with available antibiotics. MDCO IDC encompasses basic research and drug discovery focused on bacterial mechanisms of drug resistance; drug development focused on the most threatening bacterial diseases; and a distribution and commercial infrastructure that serves the leading hospitals and healthcare facilities in the United States. MDCO IDC recently received approval for VABOMERE for the treatment of complicated urinary tract infections in adults caused by designated susceptible Enterobacteriaceae, including those resistant to currently available carbapenems. MDCO IDC has a leading pipeline of novel agents directed towards existing and emerging multidrug-resistant bacteria.
In addition to the development and approval of VABOMERE, MDCO IDC has, since 2014, successfully received approval for and launched two antibiotics against serious infections: ORBACTIV® (oritavancin) for the treatment of acute bacterial skin and skin-structure infections in adults, caused by designated pathogens, including methicillin-resistant Staphylococcus aureus, and a new formulation of MINOCIN® (minocycline) for Injection, which is among the few FDA-approved agents for the treatment of infections due to Acinetobacter spp., a pathogen classified by the CDC to be a serious antimicrobial resistance threat. For more information on these products, including their respective important safety information and package inserts, please see www.orbactiv.com and www.minociniv.com.
In February 2014, The Medicines Company Infectious Disease Business was awarded a cost-sharing contract by the Biomedical Advanced Research and Development Authority (BARDA), a division of the Office of the Assistant Secretary for Preparedness and Response within the U.S. Department of Health and Human Services (HHS), of which $55.8 million in federal funds have been obligated to date to support the development of VABOMERE.
In September 2016, The Medicines Company entered into a new strategic partnership with BARDA that will provide the Company with the potential for up to $132 million to support the development of new antibiotics to fight drug-resistant, gram-negative infections (HHSO100201600026C). The partnership was established under HHS’s Other Transactional Authority (OTA), and is a distinctive, flexible, portfolio-based approach to funding drug development. The Medicines Company was awarded $32 million in initial funding, and up to an additional $100 million (pending the availability of funding) over approximately five years, if all options to extend the partnership are exercised by BARDA and The Medicines Company. The initial $32 million award supports further development of VABOMERE as well as advancement of the Company’s early stage pipeline. Funding provided under any subsequent options exercised by BARDA and The Medicines Company, will also support the advancement of antibiotics in MDCO IDC’s portfolio of new antibiotic drug candidates targeting drug resistant bacteria.
About The Medicines Company
The Medicines Company is a biopharmaceutical company driven by an overriding purpose – to save lives, alleviate suffering and contribute to the economics of healthcare. The Company’s mission is to create transformational solutions to address the most pressing healthcare needs facing patients, physicians and providers in serious infectious disease care and cardiovascular care. The Company is headquartered in Parsippany, New Jersey, with a global innovation center in California.
Statements contained in this press release that are not purely historical may be deemed to be forward-looking statements for purposes of the safe harbor provisions under The Private Securities Litigation Reform Act of 1995. Without limiting the foregoing, the words "believes," "anticipates," "expects," “potential,” and similar expressions are intended to identify forward-looking statements. These forward-looking statements involve known and unknown risks and uncertainties that may cause the Company's actual results, levels of activity, performance or achievements to be materially different from those expressed or implied by these forward-looking statements. Important factors that may cause or contribute to such differences include whether clinical trials will advance on a timely basis, or at all, or succeed in achieving their specified endpoints; whether physicians, patients and other key decision makers will accept clinical trial results; whether the Company will make regulatory submissions on a timely basis, or at all; whether the Company’s regulatory submissions will receive approvals from regulatory agencies on a timely basis, or at all; and such other factors as are set forth in the risk factors detailed from time to time in the Company's periodic reports and registration statements filed with the Securities and Exchange Commission, including, without limitation, the risk factors detailed in the Company's Quarterly Report on Form 10-Q filed with the Securities and Exchange Commission on August 9, 2017, which are incorporated herein by reference. The Company specifically disclaims any obligation to update these forward-looking statements.